CN1087609C - Chalcones and their esters with antiproliferative activity of uterine, ovarian and breast tumors - Google Patents
Chalcones and their esters with antiproliferative activity of uterine, ovarian and breast tumors Download PDFInfo
- Publication number
- CN1087609C CN1087609C CN95196940A CN95196940A CN1087609C CN 1087609 C CN1087609 C CN 1087609C CN 95196940 A CN95196940 A CN 95196940A CN 95196940 A CN95196940 A CN 95196940A CN 1087609 C CN1087609 C CN 1087609C
- Authority
- CN
- China
- Prior art keywords
- hydroxyl
- cordoin
- chalcone derivative
- derris extract
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Plant Substances (AREA)
- Indole Compounds (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention relates to the use of natural or synthetic chalcones and esters thereof with linear or branched fatty acids, saturated or unsaturated, containing up to 22 carbon atoms, for the treatment and prevention of uterine, ovarian and breast tumors, and to compositions containing them. Chalcones such as isocycoin, brevicin, 2-hydroxyderlin, 2 ', 4' -dihydroxychalcone, 4, 2 ', 4' -trihydroxychalcone have a significant affinity for type II estrogen receptors, while having antiproliferative activity on uterine, ovarian and breast tumor cell lines. These molecules have proven useful in both the treatment and prevention of such tumors.
Description
The present invention relates to chalcone compounds and with saturated or undersaturated, contain the application of ester in treatment and prevention uterus, ovary and breast tumor that the straight or branched fatty acid that reaches 22 carbon atoms forms, also relate to the compositions that contains them.
Recently, some flavonoid are proved have active anticancer (Cancer Research 48,5754,1988) and the chemoprophylaxis activity in some tumors (J.Nat.Prod.53,23,1990).Especially a kind of flavonoid-Quercetin skin ketone that extensively are present in the plant except having the synergistic activity with traditional chemotherapy, also demonstrate some to human blood cell (Br.J.of Haematology 75,489,1990) and other cell line (Br.J.Cancer 62,942,1990-1nt.J.Cancer 46,1112,1990-CancerChemother.Pharmacol.28,255,1991-Gynecologic Oncology 45,13,1991,1992) outgrowth inhibition is active.As if although also do not know thisly to outgrowth inhibiting mechanism, it is relevant with the interaction of this flavonoid and II type estrogen receptor (J.Steroid Biochem.30,71,1988).Clark (J.Biol.Chem.253,7630,1978) at first these sites in the rat uterus are described in 1978, although they demonstrate identical steroid and tissue specificity, but have tangible different with " real " estrogen receptor (ER), because their concentration ratio ER height, and the apparent affine dissociation constant (kD:10-20nM) lower than ER (kD:0.2-1nM) arranged for estradiol.
We are surprised to find now, chemical compound with chalcone derivative structure be Flemistrictin A (isocordoin), 4-hydroxyl derris extract (4-hydroxy derricin), 2-hydroxyl derris extract, 3-hydroxyl derris extract, 2 ', 4 '-dihydroxy chalcone derivative, 4 ', 2 ', 4 '-trihydroxy chalcone derivative and Cordoin (cordoin) have significant affinity to II type estrogen receptor, affinity than known product is high a lot, and they have tangible anti-proliferative activity to uterus, ovary and breast tumor cell line simultaneously.
Above-mentioned compound structure is as follows:
R
1 R
2 R
3 R
4 R
5
S1 Flemistrictin A H H prenyl H H
S2 4-hydroxyl derris extract Me OH prenyl H H
S3 2-hydroxyl derris extract Me H prenyl OH H
S4 3-hydroxyl derris extract Me H prenyl H OH
S5?2′，4′-
Dihydroxy chalcone derivative H H H H H
S6?4，2′，4′-
Trihydroxy chalcone derivative H OH H H H
S7 Cordoin prenyl H H H H
With strict other the relevant chalcone derivative of above-mentioned substance, as 4-hydroxyl Cordoin and dihydro Cordoin with structure as follows do not have affinity to above-mentioned receptor on chemical constitution.
Chalcone derivative R
1R
2R
3
S8 4-hydroxyl Cordoin prenyl OH H
S9 dihydro Cordoin prenyl H H
Thereby an aspect of of the present present invention provides formula (I) chemical compound to have application, the especially application when handling the tumor of expressing II type estrogen receptor in the medicine of active anticancer in preparation.
In addition, another aspect of the present invention also provides formula (I) chemical compound and ester saturated or undersaturated, that contain the straight or branched fatty acid formation that reaches 22 carbon atoms.Particularly preferably be the ester that forms with acetic acid, butanoic acid, Palmic acid or ximenic acid (ximeninic acid).
Ester of the present invention can pass through oral administration, and they are seemingly as the former medicine effect of chalcone derivative I.
At last, the invention provides the pharmaceutical composition that contains as the Compound I of active component or its ester and suitable excipient.
By by Il Farmaco, 30,449-55,1975; Il Farmaco, 32,261-69,1977; Il Farmaco, 30,326-42, the traditional method of 1975 reports can prepare chemical compound (I).
Compound I is reported in following table the anti-proliferative activity of ovarian tumor cell the affinity of II type estrogen receptor and it.
The table-to II type estrogen receptor in conjunction with affinity with at external anti-proliferative activity to OVCA 433 cancerous cell
Chalcone derivative IC
50.. (uM) IC
50... (uM)
S1 1.2 1.2
S2 17.0 10.6
S3 4.2 18.0
S4 5.0 12.1
S5 2.5 0.6
S6 5.0 3.2
S7 6.0 4.2
Concentration when .. the pair cell hypertrophy has 50% inhibitory action.
... the concentration when from receptor, displacing the estradiol (40nM) of 50% labelling.
Estrogen receptor is in conjunction with estimating on the tumor cell of ovary and other organ.Cell is grown in the culture of monolayer, and used culture medium is to add the penicillin of calf serum and 200 units/ml to keep culture medium aseptic in minimum essential medium.In order to make test have repeatability, use the trypsin treatment cell weekly and with 8 * 10
-4Density be placed on the culture dish, at the CO that contains 5%
2Atmosphere in and under certain humidity, cultivate down at 37 ℃.In order to measure the activity of chemical compound, will in minimum culture medium, concentration be 1 * 10
-5The cell of/ml places in the hole (Falcon 3046, Becton Dickinson NY).After 24 hours, replace old culture medium and the chalcone derivative that will be dissolved in the straight alcohol adds with fresh culture.Handle matched group similarly with carrier, just wherein do not contain detected active component.Above-mentioned processing method repeated once every 24 hours in 72 hours detection time.After 24 hours, use separately scalar labelling estradiol (
3H-E
240Ci/mmol Amershan UK) or under the situation that 100 times diethylstilbestrol exists under 4 ℃ with cell culture 2.5 hours.When cultivate finishing, cell is got express developed and with the NaOH cultivation of 1M 30 minutes with fresh culture.Measure radioactivity and come the calculations incorporated specificity by scintiloscope by the difference between the preparation that contains and do not contain diethylstilbestrol.According to traditional method, the result is expressed as the binding site number of each cell.The outgrowth inhibiting evaluation of pair cell is to carry out direct cell counting by the growing state to matched group and processed group to carry out.
Chemical compound of the present invention is under the said in the literature generic condition to the outgrowth inhibition of cells in vivo, confirms by the size of measuring the intravital tumor of implantation athymic mouse.Dosage with 1 to 100mg/kg carries out processes and displays to animal, and observed tumor has significantly and reduces, until complete obiteration in most of individuality.For the people, Compound I has higher activity than known drug such as tamoxifen to ovary, mammary gland and uterus tumor.
In above-mentioned detection, Flemistrictin A, Cordoin and 2 ', 4 '-ester of dihydroxy chalcone derivative demonstrates very significant activity.
Chemical compound of the present invention can be by preferably oral or perfusion administration; For oral administration, it is very useful that natural or synthetic phospholipid is proved to be, because they and chalcone derivative have formed stable fat-soluble complex; Medium chain triglyceride also is proved to be useful with relevant excipient.The using dosage of The compounds of this invention can change in very wide scope, for example from 10 to 300mg/ days, mainly passes through oral administration.
The following example further illustrates the present invention.
The preparation of example I-ximenic acid Cordoin ester
Under 60-70 ℃, 7g 4-O-prenyl-2-hydroxy acetophenone and 7g benzaldehyde react in 10g piperidines and 70ml ethanol.After 36 hours, under vacuum solvent is removed, residue dissolves with the 100ml benzene that fully cleans through 2N HCl.After benzene removed, residue is purified in silicagel column, obtain the 3.5g Cordoin.The Cordoin that obtains is reacted with 3g chlorination ximenic acid in the 20ml anhydrous pyridine.Reactant mixture poured in the water and with dichloromethane product is extracted.Obtain 4.2g ximenic acid Cordoin ester from methanol after the crystallization, its fusing point is 164-166 ℃.
The preparation of example II-Palmic acid Flemistrictin A ester
Under 60 ℃, be dissolved in 10g 3-C-prenyl resacetophenone and 10g hydroxy benzaldehyde in 15g piperidines and the 200ml straight alcohol and kept 4 hours.After solvent removed, residue is suspended among the 50ml 2N HCl and with dichloromethane extracting product.After chlorating solvent removed, with the silica gel residue of purifying, obtain the 4.1g Flemistrictin A, its fusing point is 160-1 ℃.This product is reacted with the 8g Hexadecanoyl chloride in the 30ml anhydrous pyridine.With the reactant mixture dilute with water and with after the silica gel purification, obtain 6.2g two palmityl Flemistrictin As, its fusing point is 131-132 ℃.
The preparation of EXAMPLE III-acetic acid Cordoin ester, acetic acid Flemistrictin A ester and butanoic acid Cordoin ester, butanoic acid Flemistrictin A ester
These products are according to example I and II, use the chloride of respective acids or anhydride to prepare respectively.(131-3 ℃ of acetic acid Cordoin ester fusing point; 124-6 ℃ of butanoic acid Cordoin ester fusing point).
The preparation of the complex of EXAMPLE IV-Flemistrictin A and dipalmitoyl phosphatidyl choline.
The 3.08g Flemistrictin A is suspended in the dichloromethane of 30ml and adds the 7.9g dipalmitoyl phosphatidyl choline, under agitation reacted 1 hour.After reagent dissolves fully, reactant mixture is concentrated into smaller size smaller also this concentrate is poured in the 50ml normal hexane.The solid matter of separating out is filtered and spend the night at 40 times vacuum dryings, obtain 7.2g phospholipid Flemistrictin A complex, its fusing point is 70 ℃.
Claims (5)
- By Flemistrictin A, Cordoin, 4-hydroxyl derris extract, 2-hydroxyl derris extract, 3-hydroxyl derris extract, 2 ', 4 '-dihydroxy chalcone derivative or 4,2 ', 4 '-ester that trihydroxy chalcone derivative and acetic acid, butanoic acid, Palmic acid or ximenic acid form.
- 2. according to the Cordoin or the Flemistrictin A ester of claim 1.
- Flemistrictin A, Cordoin, 4-hydroxyl derris extract, 2-hydroxyl derris extract, 3-hydroxyl derris extract, 2 ', 4 '-dihydroxy chalcone derivative or 4,2 ', 4 '-ester that trihydroxy chalcone derivative and acetic acid, butanoic acid, Palmic acid or ximenic acid form is used for the treatment of or prevents application in the medicine of ovary, mammary gland and uterus tumor in preparation.
- Flemistrictin A, Cordoin, 4-hydroxyl derris extract, 2-hydroxyl derris extract, 3-hydroxyl derris extract, 2 ', 4 '-dihydroxy chalcone derivative or 4,2 ', 4 '-complex of trihydroxy chalcone derivative and natural or synthetic phospholipid.
- 5. be used for the treatment of or prevent the pharmaceutical composition of ovary, mammary gland and uterus tumor, it contain as the Flemistrictin A among the claim 1-2 of active component, Cordoin, 4-hydroxyl derris extract, 2-hydroxyl derris extract, 3-hydroxyl derris extract, 2 ', 4 '-dihydroxy chalcone derivative or 4,2 ', 4 '-ester or the complex in the claim 4 and the suitable excipient of trihydroxy chalcone derivative.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI942568A IT1271301B (en) | 1994-12-20 | 1994-12-20 | NATURAL AND SYNTHETIC CALCONES AND THEIR ESTERS WITH ANTI-PROLIFERATIVE ACTIVITY IN CANCER OF THE UTERUS, OVARIAN AND BREAST AND FORMULATIONS CONTAINING THEM |
| ITMI94A002568 | 1994-12-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1170362A CN1170362A (en) | 1998-01-14 |
| CN1087609C true CN1087609C (en) | 2002-07-17 |
Family
ID=11370023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95196940A Expired - Fee Related CN1087609C (en) | 1994-12-20 | 1995-12-04 | Chalcones and their esters with antiproliferative activity of uterine, ovarian and breast tumors |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5808137A (en) |
| EP (1) | EP0800387B1 (en) |
| JP (1) | JP2004131509A (en) |
| KR (1) | KR100264369B1 (en) |
| CN (1) | CN1087609C (en) |
| AT (1) | ATE222756T1 (en) |
| AU (1) | AU689357B2 (en) |
| CA (1) | CA2208351C (en) |
| CZ (1) | CZ288043B6 (en) |
| DE (1) | DE69527980T2 (en) |
| DK (1) | DK0800387T3 (en) |
| ES (1) | ES2181806T3 (en) |
| FI (1) | FI972641A7 (en) |
| HU (1) | HU225501B1 (en) |
| IT (1) | IT1271301B (en) |
| NO (1) | NO307926B1 (en) |
| PL (1) | PL183772B1 (en) |
| PT (1) | PT800387E (en) |
| RU (1) | RU2181284C2 (en) |
| SI (1) | SI9520139B (en) |
| SK (1) | SK282259B6 (en) |
| WO (1) | WO1996019209A1 (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9712966D0 (en) * | 1997-06-19 | 1997-08-27 | Indena Spa | Novel chalcones |
| US6423740B1 (en) | 1997-06-19 | 2002-07-23 | Indena S.P.A. | Chalcones having antiproliferative activity |
| US6239114B1 (en) * | 1997-09-26 | 2001-05-29 | Kgk Synergize | Compositions and methods for treatment of neoplastic diseases with combinations of limonoids, flavonoids and tocotrienols |
| GB9920910D0 (en) | 1999-09-03 | 1999-11-10 | Indena Spa | Novel chalcones |
| GB9920908D0 (en) | 1999-09-03 | 1999-11-10 | Indena Spa | Chalcone coumarins |
| US6545007B2 (en) | 2000-11-17 | 2003-04-08 | Idenix (Cayman) Limited | Methods for inhibiting the transmission of HIV using topically applied substituted 6-benzyl-4-oxopyrimidines |
| IL153565A0 (en) | 2000-06-20 | 2003-07-06 | Atherogenics Inc | 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat vcam-1 mediated disorders |
| RU2004121898A (en) * | 2001-12-19 | 2006-01-20 | Атеродженикс, Инк. (Us) | CHALKONE DERIVATIVES AND THEIR APPLICATION FOR TREATMENT OF DISEASES |
| US7514579B2 (en) * | 2002-06-13 | 2009-04-07 | Johns Hopkins University | Boronic chalcone derivatives and uses thereof |
| WO2004056727A2 (en) * | 2002-12-19 | 2004-07-08 | Atherogenics, Inc. | Process of making chalcone derivatives |
| KR20060121273A (en) | 2003-12-05 | 2006-11-28 | 다카라 바이오 가부시키가이샤 | remedy |
| US20060063828A1 (en) * | 2004-06-28 | 2006-03-23 | Weingarten M D | 1,2-Bis-(substituted-phenyl)-2-propen-1-ones and pharmaceutical compositions thereof |
| CN100336797C (en) * | 2005-08-19 | 2007-09-12 | 浙江大学 | Tetra substituted chalcone derivative and preparing method and use |
| GB0609386D0 (en) * | 2006-05-11 | 2006-06-21 | Active Botan Ltd | Treating drug resistant cancers |
| US9132117B2 (en) | 2013-06-17 | 2015-09-15 | Kgk Synergize, Inc | Compositions and methods for glycemic control of subjects with impaired fasting glucose |
| ES2540457B2 (en) * | 2013-06-19 | 2015-12-28 | Universidad De Sevilla | Procedure for obtaining leaf extracts from Corema album and its therapeutic application |
| KR101731159B1 (en) | 2015-02-04 | 2017-04-28 | 계명대학교 산학협력단 | Antifungal composition comprising 2',4'-dihydroxychalcone compound |
| CZ307046B6 (en) * | 2015-09-02 | 2017-12-13 | Univerzita Palackého v Olomouci | Copper complexes with derivatives of (E)-1-(2'-hydroxyphenyl)-3-phenyl-prop-2-en-1-one and their use as pharmaceuticals in antitumour therapy |
| CN111138264B (en) * | 2019-11-29 | 2023-08-04 | 温州医科大学 | Syringaldehyde derivative and application thereof in preparing anti-gynecological tumor drugs |
| CN113564103B (en) * | 2021-05-17 | 2023-01-06 | 南京医科大学 | Application of 4,4'-dimethoxychalcone in delaying oocyte aging in vitro and in vivo |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991017749A1 (en) * | 1990-05-17 | 1991-11-28 | Baylor College Of Medicine | Growth inhibitors and methods of treating cancer and cell proliferative diseases |
| WO1993001824A1 (en) * | 1991-07-24 | 1993-02-04 | Baylor College Of Medicine | Combination therapy using bioflavonoid compounds with anti-cancer drugs |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH593224A5 (en) * | 1973-10-30 | 1977-11-30 | Taisho Pharmaceutical Co Ltd | |
| US5234951A (en) * | 1986-12-12 | 1993-08-10 | Tsumura Juntendo, Inc. | Anti-ulcer agent comprising chalcone derivative |
| WO1988004288A1 (en) * | 1986-12-12 | 1988-06-16 | Tsumura Juntendo, Inc. | Anti-ulcerous agent containing chalcone derivative as effective ingredient and novel chalcone derivatives |
-
1994
- 1994-12-20 IT ITMI942568A patent/IT1271301B/en active IP Right Grant
-
1995
- 1995-12-04 US US08/849,767 patent/US5808137A/en not_active Expired - Fee Related
- 1995-12-04 KR KR1019970704130A patent/KR100264369B1/en not_active Expired - Fee Related
- 1995-12-04 WO PCT/EP1995/004770 patent/WO1996019209A1/en not_active Ceased
- 1995-12-04 EP EP95941665A patent/EP0800387B1/en not_active Expired - Lifetime
- 1995-12-04 CA CA002208351A patent/CA2208351C/en not_active Expired - Fee Related
- 1995-12-04 RU RU97112461/14A patent/RU2181284C2/en not_active IP Right Cessation
- 1995-12-04 AT AT95941665T patent/ATE222756T1/en not_active IP Right Cessation
- 1995-12-04 SK SK781-97A patent/SK282259B6/en unknown
- 1995-12-04 ES ES95941665T patent/ES2181806T3/en not_active Expired - Lifetime
- 1995-12-04 CZ CZ19971869A patent/CZ288043B6/en not_active IP Right Cessation
- 1995-12-04 HU HU9702094A patent/HU225501B1/en not_active IP Right Cessation
- 1995-12-04 DE DE69527980T patent/DE69527980T2/en not_active Expired - Fee Related
- 1995-12-04 PL PL95320787A patent/PL183772B1/en not_active IP Right Cessation
- 1995-12-04 FI FI972641A patent/FI972641A7/en unknown
- 1995-12-04 CN CN95196940A patent/CN1087609C/en not_active Expired - Fee Related
- 1995-12-04 PT PT95941665T patent/PT800387E/en unknown
- 1995-12-04 AU AU43019/96A patent/AU689357B2/en not_active Ceased
- 1995-12-04 SI SI9520139A patent/SI9520139B/en not_active IP Right Cessation
- 1995-12-04 DK DK95941665T patent/DK0800387T3/en active
-
1997
- 1997-06-19 NO NO972842A patent/NO307926B1/en unknown
-
2003
- 2003-12-26 JP JP2003434456A patent/JP2004131509A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991017749A1 (en) * | 1990-05-17 | 1991-11-28 | Baylor College Of Medicine | Growth inhibitors and methods of treating cancer and cell proliferative diseases |
| WO1993001824A1 (en) * | 1991-07-24 | 1993-02-04 | Baylor College Of Medicine | Combination therapy using bioflavonoid compounds with anti-cancer drugs |
Non-Patent Citations (1)
| Title |
|---|
| ANTI-CANCER DRUG DES 10(4) 1995.1.1 R.De Vincenzo等"effect of synthetic and naturally occuring chalcones on ovarian cancer cell grounth * |
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